SUMMARY Proper establishment of connectivity in the nervous system is essential for higher brain functions including perception, learning and memory. Neuronal circuits are initially assembled through circuit building (progressive) events, like axon growth. Subsequently, many brain circuits require refinement of supernumerary connections via regressive events. Regressive events like axon pruning and synapse elimination play key roles in circuit maturation and refinement. Axon pruning events facilitate the removal of exuberant axonal branches, without necessarily eliciting cell death. Disruption of normal pruning events during circuit maturation has been linked to neurodevelopmental disorders, ranging from autism to schizophrenia. Despite playing a key role in both the etiology of these disorders and maturation of a healthy nervous system, the underlying cellular mechanisms behind pruning events remain largely unknown. Gaining insight into these mechanisms is instrumental for advancing our understanding of neurodevelopmental disorders. Therefore the long-term goal of this project is to elucidate the molecular mechanisms responsible for refining brain connectivity, with a particular emphasis on neuronal circuits critical for normal cognitive function. To achieve this long-term goal, we propose to map and characterize caspase-dependent neuronal refinement events in neurons that survive but prune their connections. The proposed studies will generate a powerful new tool to investigate caspase-dependent circuit refinement. This tool will have broad applicability to study development and disease in a variety of organs. Successful accomplishment of these objectives will have important implications for defining the location and prevalence of caspase-dependent pruning in vivo, a developmental process essential for the establishment and refinement of neural circuits. In the future, we will take advantage of the innovative approaches generated as part of this proposal to identify novel molecular players required for circuit maturation. !